PROJECT SUMMARY While diabetes has reached epidemic levels, respiratory infections, such as influenza, have long held a high spot on the list of worldwide causes of death. Diabetes, which is defined by a persistent hyperglycemic state, leads to multiple organ complications. Importantly, hyperglycemia is a major and independent risk factor for the development and worsening severity of pulmonary infection, including influenza infection. This phenomenon is thought to occur due to the hyperglycemic state predisposing patients to a higher-than-normal glucose concentration in the airway, leading to an increased risk of pulmonary infections. Although the lung is a major organ to utilize glucose, the role and the regulation of glucose homeostasis in the lung have received little attention. Therefore, our long-term goal is to investigate the role and alterations of glucose homeostasis that occur during respiratory infections. Glucose uptake from the bloodstream, the rate-limiting in glucose utilization, is tightly regulated by a family of specialized proteins, called glucose transporters (GLUTs). Because every cell expresses these GLUTs, they are recognized as major regulators of whole-body glucose metabolism and thus are key pharmacological targets. However, little is known about the regulation of glucose transport and utilization in the respiratory system, particularly during a hyperglycemic state. Importantly, we recently demonstrated that the expression and activity of several major and novel GLUT isoforms were altered in the lung during diabetes, as well as the downstream insulin signaling pathway. We further showed that diabetic mice possess higher viral titers in the bronchial alveolar lavage fluid following influenza infection. Therefore, the overall goal of this project is to understand how alterations in pulmonary glucose homeostasis during diabetes enhance viral replication and thus the pathogenesis of influenza. The specific aims of this project are to test the hypotheses that: 1) impaired glucose transport and utilization enhances influenza infection in the lungs of diabetic animals; and 2) alterations of the insulin signaling pathway in the diabetic lung enhance the inflammatory response and the severity of influenza infection. We will use a comprehensive, integrated approach at multiple system levels using state-of-the-art techniques and the CoBRE Core Facilities. An interdisciplinary mentoring team will also provide the applicant with an intensive collaborative research experience in the rich intellectual environment at Oklahoma State University and at the University of Oklahoma Health Sciences Center. Insights gained from this study could lead us 1) to establish a novel mechanistic link between diabetes and influenza infections; and 2) to identify novel metabolic therapeutic targets for viral influenza infections, a crucial outcome of this project. Finally, by capitalizing on her strong dual training in basic and clinical sciences, this award is designed to foster the development of the applicant toward achieving her career goals in the field of respiratory and infectious diseases.